WO2005051296A2 - Fused ring dicationic anti-protozoan agents and their prodrugs - Google Patents
Fused ring dicationic anti-protozoan agents and their prodrugs Download PDFInfo
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- WO2005051296A2 WO2005051296A2 PCT/US2004/038896 US2004038896W WO2005051296A2 WO 2005051296 A2 WO2005051296 A2 WO 2005051296A2 US 2004038896 W US2004038896 W US 2004038896W WO 2005051296 A2 WO2005051296 A2 WO 2005051296A2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
- C07D219/08—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
- C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
- C07C291/04—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds containing amino-oxide bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/24—Anthracenes; Hydrogenated anthracenes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the presently disclosed subject matter relates to methods of combating microbial infections with dicationic compounds. More particularly, the presently disclosed subject matter relates to methods of combating microbial infections with fused ring dicationic compounds, and to the novel compounds themselves.
- Na 2 SO 4 sodium sulfate
- NBS ⁇ /-bromosuccinimide
- T. br. Trypanosoma brucei rhodesiense
- TLC thin-layer chromatography
- Pentamidine has been used clinically against African trypanosomiasis, antimony-resistant leishmaniasis, and P. carinii pneumonia. See, e.g., Apted.
- Ri and R 2 are each independently selected from the group consisting of H, alkyl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl;
- m and n are integers from 0 to 3, provided that when m is zero, Ri is an implied hydrogen, and when n is zero, R 2 is an implied hydrogen;
- p and q are integers from 0 to 1 ;
- a and A' are each independently selected from one of:
- R4, R 5 , Re, R 7 , and R & are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; or R 5 and Re together represent a C 2 to C 10 alkyl, hydroxyalkyl, or alkylene; or R 8 is Re — N R, wherein: Rg and R 10 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: R 11 is selected from the group consisting of H, alkyl, and aryl.
- the presently disclosed subject matter relates to a pharmaceutical formulation comprising a compound of Formula I in a pharmaceutically acceptable carrier. In some embodiments, the presently disclosed subject matter relates to a method of treating a microbial infection, comprising administering an effective amount of a compound of Formula I to a subject in need thereof. In some embodiments, the presently disclosed subject matter relates to the use of an active compound as described hereinabove (i.e., a compound of
- Formula l)forthe preparation of a medicament for treating a microbial infection provides compounds that are useful in the treatment of microbial infections.
- the presently disclosed subject matter provides pharmaceutical formulations for use in the treatment of microbial infections.
- the presently disclosed subject matter provides methods for treating microbial infections.
- alkyl refers to C 1 - 20 inclusive, linear (i.e., "straight-chain"), branched, or cyclic, saturated or at least partially and in some cases fully unsaturated (i.e., alkenyl and alkynyl) hydrocarbon chains, including for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and allenyl groups.
- Branched refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain.
- Lower alkyl refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C-i- ⁇ alkyl), i.e., 1 , 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
- Higher alkyl refers to an alkyl group having about 10 to about
- alkyl refers, in particular, to C- ⁇ - 8 straight-chain alkyls. In other embodiments, “alkyl” refers, in particular, to Ci -8 branched-chain alkyls. Alkyl groups can be optionally substituted with one or more alkyl group substituents, which can be the same or different.
- alkyl group substituent includes but is not limited to alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl.
- nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl”), or aryl.
- aryl is used herein to refer to an aromatic substituent that can be a single aromatic ring, or multiple aromatic rings that are fused together, linked covalently, or linked to a common group such as a methylene or ethylene moiety.
- the common linking group also can be a carbonyl as in benzophenone or oxygen as in diphenylether or nitrogen as in diphenylamine.
- aryl specifically encompasses heterocyclic aromatic compounds.
- the aromatic ring(s) can comprise phenyl, naphthyl, biphenyl, diphenylether, diphenylamine and benzophenone, among others.
- aryl means a cyclic aromatic comprising from about 5 to about 10 carbon atoms, i.e., 5, 6, 7, 8, 9, or 10 carbon atoms, and including 5- and 6-membered hydrocarbon and heterocyclic aromatic rings.
- the aryl group can be optionally substituted with one or more aryl group substituents which can be the same or different, wherein "aryl group substituent" includes alkyl, aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkyloxyl, carboxyl, acyl, halo, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, alkylene, and -NR'R", wherein R' and R" can be each independently hydrogen, alkyl, aryl, and aralkyl.
- aryl groups include but are not limited to cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline, indole, carbazole, and the like.
- a dashed line representing a bond in an aryl group indicates that the bond is either present or absent depending on the number of atoms comprising the aromatic ring and, in the case of a heterocyclic aromatic ring, the identity of the heteroatom.
- substituted alkyl and “substituted aryl” include alkyl and aryl groups, as defined herein, in which one or more atoms or functional groups of the aryl or alkyl group are replaced with another atom or functional group, including for example, halogen, aryl, alkyl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.
- acyl refers to an organic acid group wherein the -OH of the carboxyl group has been replaced with another substituent (i.e., as represented by RCO — , wherein R is an alkyl or an aryl group as defined herein).
- RCO substituent
- acyl specifically includes arylacyl groups.
- Specific examples of acyl groups include acetyl and benzoyl.
- Cyclic and “cycloalkyl” refer to a non-aromatic mono- or multi-cyclic ring system of about 3 to about 10 carbon atoms, i.e., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
- the cycloalkyl group can be optionally partially unsaturated.
- the cycloalkyl group can be also optionally substituted with an alkyl group substituent as defined herein, oxo, and/or alkylene. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl, or aryl, thus providing a heterocyclic group.
- Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl.
- Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl.
- Alkoxyl or “alkoxyalkyl” refer to an alkyl-O- group wherein alkyl is as previously described.
- alkoxyl as used herein can refer to C ⁇ -2 o inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, f-butoxyl, and pentoxyl.
- Aryloxyl refers to an aryl-O- group wherein the aryl group is as previously described.
- aryloxyl as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.
- Aralkyl refers to an aryl-alkyl- group wherein aryl and alkyl are as previously described. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.
- “Aralkyloxyl” refers to an aralkyl-O- group wherein the aralkyl group is as previously described. An exemplary aralkyloxyl group is benzyloxyl.
- “Pialkylamino” refers to an -NRR' group wherein each of R and R' is independently an alkyl group as previously described.
- Exemplary alkylamino groups include ethylmethylamino, dimethylamino, and diethylamino.
- Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and f-butyloxycarbonyl.
- An alkoxycarbonyl group can be further represented by the following structural formula: O II — C-O-R wherein the "R" group represents an alkyl group as defined hereinabove.
- alkoxycarbonyl group also can be referred to as an "alkyl ester" group.
- R is an ethyl group and the alkoxycarbonyl group comprises the following formula: O II — C-0-CH 2 CH 3
- “Acyloxyl” refers to an acyl-O- group wherein acyl is as previously described.
- Acylamino refers to an acyl-NH- group wherein acyl is as previously described.
- “Aroylamino” refers to an aroyl-NH- group wherein aroyl is as previously described.
- Alkylene refers to a straight or branched bivalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms, i.e., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
- the alkylene group can be straight, branched or cyclic.
- the alkylene group can be also optionally unsaturated and/or substituted with one or more "alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described.
- Exemplary alkylene groups include methylene (-CH 2 -); ethylene
- alkylene group can have about 2 to about 3 carbon atoms and can further have
- amino refers to the -NH 2 group.
- halo refers to fluoro, chloro, bromo, and iodo groups.
- hydroxyl refers to the -OH group.
- hydroxyalkyl refers to an alkyl group substituted with an -OH group.
- mercapto refers to the -SH group.
- oxo refers to a compound described previously herein wherein a carbon atom is replaced by an oxygen atom.
- nitro refers to the -N0 2 group.
- thio refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.
- sulfate refers to the -S0 4 group.
- X and Y are each independently selected from the group consisting of CH, CH 2 , N, CO, O, S, and NR 3 , wherein R 3 is selected from the group consisting of H, alkyl, aryl, alkoxyl, and aryloxyl, and Y can be present or absent;
- R-i and R 2 are each independently selected from the group consisting of H, alkyl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl;
- m and n are integers from 0 to 3, provided that when m is zero, Ri is an implied hydrogen, and when n is zero, R 2 is an implied hydrogen;
- p and q are integers from 0 to 1 ;
- a and A' are each independently selected from one of:
- R 4 , R 5 , Re, R7, and R 8 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; or R 5 and R & together represent a C 2 to C 10 alkyl, hydroxyalkyl, or alkylene; or Re is R 9 — N ⁇ R 10 wherein: R 9 and R 10 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: R 11 is selected from the group consisting of H, alkyl, and aryl.
- X is CH 2 and Y is absent.
- the fused-ring structure comprises 9H-fluorene.
- a and A' are each independently
- R and R are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; and Re is selected from the group consisting of aryl and
- R 9 and R ⁇ 0 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: R 11 is selected from the group consisting of H, alkyl, and aryl.
- a and A' are in the 2- and 7-positions of the 9H-fluorene ring.
- m and n are both zero and R 7 is H.
- R 4 is H and Re is phenyl.
- R 4 is H and R 8 is 2-pyridyl.
- R 8 is
- Rg and Rio are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: R1 1 is selected from the group consisting of H, alkyl, and aryl.
- R 4 and Rg are each H.
- R 4 is ethoxycarbonyl and R 9 is H.
- Rio is H.
- R 10 is methyl.
- 0 isopropyl.
- R-io is methoxyl.
- Rio is iso-butoxyl.
- the fused-ring structure comprises 9H-fluoren-9- one.
- a and A' are each independently
- R 4 and R 7 are each independently selected from the group consisting of H alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; and R 8 is selected from the group consisting of aryl and R 9 — N ⁇ R 10 wherein: Rg and R1 0 are each independently selected from the group consisting of H, alkyl, aryl, and -OR- ⁇ ; and wherein: R 11 is selected from the group consisting of H, alkyl, and aryl.
- a and A' are in the 2- and 7-positions of the 9H-fluoren- 9-one ring.
- m and n are both zero and R is H.
- R 8 is
- Rg and R ⁇ 0 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: R 11 is selected from the group consisting of H, alkyl, and aryl.
- Rg and Rio are both H.
- R 4 is H.
- R 4 is ethoxycarbonyl.
- the fused-ring structure comprises 9,10- anthraquinone.
- a and A' are each independently
- R 4 and R 7 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; and R 8 is selected from the group consisting of aryl and R 9 — N ⁇ Rl ° wherein: Rg and R1 0 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: Rn is selected from the group consisting of H, alkyl, and aryl.
- n and n are both zero and R 7 is H. In some embodiments, R 8 is
- Rg and Rio are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: R 11 is selected from the group consisting of H, alkyl, and aryl.
- Rg and Rio are both H.
- R is H.
- X is N and Y is CH.
- the fused-ring structure comprises acridine.
- a and A' are each independently
- R 4 and R 7 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; and R 8 is selected from the group consisting of aryl and Re — N ⁇ R 10 wherein: Rg and R ⁇ 0 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: R 11 is selected from the group consisting of H, alkyl, and aryl.
- a and A' are in the 3- and 6-positions of the acridine ring.
- m and n are both zero and R is H.
- R 8 is
- Rg and R-io are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: Rn is selected from the group consisting of H, alkyl, and aryl.
- Rg and R- ⁇ 0 are both H.
- R 4 is H.
- the compound is selected from the group consisting of: 2,7-bis-guanidino-9H-fluorene; 2,7-bis- guanidinofluoren-9-one; 2,7-bis-guanidinoanthraquinone; 3,6-bis- guanidinoacridine; 2,7-bis-( ⁇ /"-ethoxycarbonyl)guanidino-9H-fluorene; 2,7- bis(A/"-ethoxycarbonyl)guanidinofluoren-9-one; 2,7-bis( ⁇ /"-ethoxycarbonyl- ⁇ /- methyl)guanidino-9H-fluorene; 2,7-bis( ⁇ /"-ethoxycarbonyl- ⁇ /- isopropyl)guanidino-9/-/-fluorene; 2,7-bis( ⁇ /"-eth
- the compound of Formula I comprises a pharmaceutically acceptable salt.
- the salt is a hydrochloride salt.
- compounds disclosed herein are prodrugs.
- a prodrug means a compound that, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this presently disclosed subject matter or an inhibitorily active metabolite or residue thereof.
- Prodrugs can increase the bioavailability of the compounds of the presently disclosed subject matter when such compounds are administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or can enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to a metabolite species, for example.
- a biological compartment e.g., the brain or lymphatic system
- a number of the compounds (e.g., compounds 7a, 7b, 7c, 7d, 8c, and 10) discussed in Example 2 are prodrugs.
- C. Pharmaceutically Acceptable Salts Additionally, the active compounds of the presently disclosed subject matter can be administered as pharmaceutically acceptable salts.
- Such salts include the gluconate, lactate, acetate, tartarate, citrate, phosphate, borate, nitrate, sulfate, and hydrochloride salts.
- the salts of the compounds described herein can be prepared, in general, by reacting two equivalents of the base compound with the desired acid, in solution. Afterthe reaction is complete, the salts are crystallized from solution by the addition of an appropriate amount of solvent in which the salt is insoluble.
- the pharmaceutically acceptable salt is a hydrochloride salt.
- compositions comprising the aforementioned active compounds also are provided herein. These pharmaceutical formulations comprise active compounds as described herein, in a pharmaceutically acceptable carrier. Pharmaceutical formulations can be prepared for oral, intravenous, or aerosol administration as described in greater detail herein below. Also, the presently disclosed subject matter provides such active compounds that have been lyophilized and that can be reconstituted to form pharmaceutically acceptable formulations for administration, as by intravenous or intramuscular injection.
- the therapeutically effective dosage of any specific active compound will vary somewhat from compound to compound, and patient to patient, and will depend upon the condition of the patient and the route of delivery. As a general proposition, a dosage from about 0.1 mg/kg to about 50 mg/kg will have therapeutic efficacy, with all weights being calculated based upon the weight of the active compound, including the cases where a salt is employed.
- Toxicity concerns at the higher level can restrict intravenous dosages to a lower level such as up to about 10 mg/kg, with all weights being calculated based upon the weight of the active base, including the cases where a salt is employed.
- a dosage from about 10 mg/kg to about 50 mg/kg can be employed for oral administration.
- a dosage from about 0.5 mg/kg to 5 mg/kg can be employed for intramuscular injection.
- dosages range from between 1 ⁇ mol/kg to 50 ⁇ mol/kg of the compound for intravenous or oral administration.
- dosages range from between 22 ⁇ mol/kg and 33 ⁇ mol/kg of the compound for intravenous or oral administration.
- compositions as described herein can be administered orally as a solid or as a liquid, or can be administered intramuscularly or intravenously as a solution, suspension, or emulsion. Alternatively, the compounds or salts can be administered by inhalation, intravenously or intramuscularly as a liposomal suspension.
- the active compound or salt When administered through inhalation the active compound or salt should be in the form of a plurality of solid particles or droplets having, in some embodiments, a particle size from about 0.5 microns to about 5 microns, and in some embodiments, a particle size from about 1 micron to about 2 microns.
- Pharmaceutical formulations suitable for intravenous or intramuscular injection are further embodiments provided herein.
- the pharmaceutical formulations comprise a compound of Formula I described herein, a prodrug as described herein, or a pharmaceutically acceptable salt thereof, in any pharmaceutically acceptable carrier. If a solution is desired, water is the carrier of choice with respect to water-soluble compounds or salts.
- an organic vehicle such as glycerol, propylene glycol, polyethylene glycol, or mixtures thereof, can be suitable.
- the organic vehicle can contain a substantial amount of water.
- the solution in either instance can then be sterilized in a suitable manner known to those in the art, and typically by filtration through a 0.22-micron filter. Subsequent to sterilization, the solution can be dispensed into appropriate receptacles, such as depyrogenated glass vials. Of course, the dispensing is preferably done by an aseptic method. Sterilized closures can then be placed on the vials and, if desired, the vial contents can be lyophilized.
- the pharmaceutical formulations can contain other additives, such as pH-adjusting additives.
- useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate.
- the formulations can contain anti-microbial preservatives.
- Useful antimicrobial preservatives include methylparaben, propylparaben, and benzyl alcohol. The anti-microbial preservative is typically employed when the formulation is placed in a vial designed for multi-dose use.
- the pharmaceutical formulations described herein can be lyophilized using techniques well known in the art.
- an injectable, stable, sterile formulation comprising a compound of Formula I, or a salt thereof, in a unit dosage form in a sealed container.
- the compound or salt is provided in the form of a lyophilizate, which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid formulation suitable for injection thereof into a subject.
- the unit dosage form typically comprises from about 10 mg to about 10 grams of the compound salt.
- a sufficient amount of emulsifying agent which is physiologically acceptable, can be employed in sufficient quantity to emulsify the compound or salt in an aqueous carrier.
- phosphatidyl choline is phosphatidyl choline.
- Other pharmaceutical formulations can be prepared from the water- insoluble compounds disclosed herein, or salts thereof, such as aqueous base emulsions. In such an instance, the formulation will contain a sufficient amount of pharmaceutically acceptable emulsifying agent to emulsify the desired amount of the compound or salt thereof.
- Particularly useful emulsifying agents include phosphatidyl cholines, and lecithin.
- Additional embodiments provided herein include liposomal formulations of the active compounds disclosed herein. The technology for forming liposomal suspensions is well known in the art.
- the compound when the compound is an aqueous-soluble salt, using conventional liposome technology, the same can be incorporated into lipid vesicles. In such an instance, due to the water solubility of the active compound, the active compound will be substantially entrained within the hydrophilic center or core of the liposomes.
- the lipid layer employed can be of any conventional composition and can either contain cholesterol or can be cholesterol-free.
- the salt when the active compound of interest is water-insoluble, again employing conventional liposome formation technology, the salt can be substantially entrained within the hydrophobic lipid bilayer that forms the structure of the liposome. In either instance, the liposomes that are produced can be reduced in size, as through the use of standard sonication and homogenization techniques.
- the liposomal formulations containing the active compounds disclosed herein can be lyophilized to produce a lyophilizate, which can be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.
- Pharmaceutical formulations also are provided which are suitable for administration as an aerosol, by inhalation. These formulations comprise a solution or suspension of a desired compound described herein or a salt thereof, or a plurality of solid particles of the compound or salt.
- the desired formulation can be placed in a small chamber and nebulized. Nebulization can be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the compounds or salts.
- the liquid droplets or solid particles have a particle size in the range of about 0.5 microns to about 10 microns. In some embodiments, the liquid droplets or solid particles have a particle size in the range of about 0.5 to about 5 microns.
- the solid particles can be obtained by processing the solid compound or a salt thereof, in any appropriate manner known in the art, such as by micronization. In some embodiments, the size of the solid particles or droplets will be from about 1 micron to about 2 microns. In this respect, commercial nebulizers are available to achieve this purpose.
- the compounds can be administered via an aerosol suspension of respirable particles in a manner set forth in U.S. Patent No. 5,628,984, the disclosure of which is incorporated herein by reference in its entirety.
- the formulation will comprise a water-soluble active compound in a carrier that comprises water.
- a surfactant can be present, which lowers the surface tension of the formulation sufficiently to result in the formation of droplets within the desired size range when subjected to nebulization.
- water-soluble and water-insoluble active compounds are provided by the presently disclosed subject matter.
- water-soluble is meant to define any composition that is soluble in water in an amount of about 50 mg/mL, or greater.
- water-insoluble is meant to define any composition that has solubility in water of less than about 20 mg/mL.
- the presently disclosed subject matter provides a pharmaceutical formulation comprising: (a) a pharmaceutically acceptable carrier; and (b) a compound of Formula I:
- Ri and R 2 are each independently selected from the group consisting of H, alkyl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl;
- m and n are integers from 0 to 3, provided that when m is zero, R ⁇ is an implied hydrogen, and when n is zero, R 2 is an implied hydrogen;
- p and q are integers from 0 to 1 ;
- a and A' are each independently selected from one of:
- R 4 , R5, R ⁇ , R7, and R 8 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; or R 5 and R 6 together represent a C 2 to C 10 alkyl, hydroxyalkyl, or alkylene; or R 8 is Re — N R 10 wherein: Rg and R 10 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: R 11 is selected from the group consisting of H, alkyl, and aryl; or a pharmaceutically acceptable salt thereof.
- X is CH 2 and Y is absent. In such embodiments, the fused-
- R 4 and R 7 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; and R 8 is selected from the group consisting of aryl and Re — N ⁇ R 10 wherein: R 9 and R-in are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: R 11 is selected from the group consisting of H, alkyl, and aryl.
- a and A' are in the 2- and 7-positions of the 9H-fluorene ring.
- m and n are both zero and R is H.
- R 4 is H and R 8 is phenyl.
- R is H and R 8 is 2-pyridyl.
- R 8 is
- Rg and Rio are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: Rn is selected from the group consisting of H, alkyl, and aryl.
- a and A' are each independently wherein: p and q are each 1 ; R 4 and R 7 are each independently selected from the group consisting of H alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; and R 8 is selected from the group consisting of aryl and
- Rg and R 10 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: Rn is selected from the group consisting of H, alkyl, and aryl.
- a and A' are in the 2- and 7-positions of the 9H-fluoren- 9-one ring.
- m and n are both zero; and R 7 is H.
- R 8 is R ⁇ — N R 10 wherein: Rg and R 10 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: R 11 is selected from the group consisting of H, alkyl, and aryl.
- Rg and R1 0 are both H.
- R 4 is H.
- R is ethoxycarbonyl.
- the fused-ring structure comprises 9,10-anthraquinone.
- a and A' are each independently
- R 4 and R 7 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; and R 8 is selected from the group consisting of aryl and
- Rg and Rio are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: Rn is selected from the group consisting of H, alkyl, and aryl.
- m and n are both zero and R is H.
- R 8 is Re — wherein: Rg and R1 0 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: R11 is selected from the group consisting of H, alkyl, and aryl.
- Rg and R 10 are both H.
- R 4 is H.
- X is N and Y is CH.
- the fused-ring structure comprises acridine.
- a and A' are each independently
- R 4 and R 7 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; and R 8 is selected from the group consisting of aryl and
- Rg and Rio are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: R 11 is selected from the group consisting of H, alkyl, and aryl.
- a and A' are in the 3- and 6-positions of the acridine ring.
- m and n are both zero; and R is H.
- R 8 is Re — N ⁇ R 10 wherein: R 9 and R 10 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: R11 is selected from the group consisting of H, alkyl, and aryl.
- Rg and R10 are both H.
- R 4 is H.
- the compound is selected from the group consisting of: 2,7-bis- guanidino-9H-fluorene; 2,7-bis-guanidinofluoren-9-one; 2,7-bis- guanidinoanthraquinone; 3,6-bis-guanidinoacridine; 2,7-bis-( ⁇ T- ethoxycarbonyl)guanidino-9H-fluorene; 2,7-bis( ⁇ /"- ethoxycarbonyl)guanidinofluoren-9-one; 2,7-bis( ⁇ /"-ethoxycarbonyl- ⁇ /'- methyl)guanidino-9/-/-fluorene; 2,7-bis( ⁇ /"-ethoxycarbonyl-A/'- isopropyl)guanidino-9/-/-fluorene; 2,7-bis( ⁇ /"-ethoxycarbonyl-A/'- isopropyl
- Subjects with microbial infections can be treated by methods described herein. These infections can be caused by a variety of microbes, including fungi, algae, protozoa, bacteria, and viruses. Exemplary microbial infections that can be treated by the method of the presently disclosed subject matter include, but are not limited to, infections caused by Trypanosoma species (e.g., Trypanosoma brucei rhodesiense), Pneumocytsis carnii, Giardia lamblia,
- compositions of Formula I are defined as having a structure as follows:
- Ri and R 2 are each independently selected from the group consisting of H, alkyl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl;
- m and n are integers from 0 to 3, provided that when m is zero, Ri is an implied hydrogen, and when n is zero, R 2 is an implied hydrogen;
- p and q are integers from 0 to 1 ;
- a and A' are each independently selected from one of: wherein: R 4 , R5.
- R 7 . and R 8 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; or R 5 and R 6 together represent a C 2 to C 10 alkyl, hydroxyalkyl, or alkylene; or R 8 is Re — N R 10 wherein: Rg and R 10 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: R 11 is selected from the group consisting of H, alkyl, and aryl; or a pharmaceutically acceptable salt thereof.
- X is CH 2 and Y is absent.
- the fused-ring structure comprises 9/-/-fluorene.
- a and A' are each independently
- R 4 and R 7 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; and R 8 is selected from the group consisting of aryl and 7 Re — N ⁇ R 10 wherein: R 9 and R ⁇ 0 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: Rn is selected from the group consisting of H, alkyl, and aryl.
- a and A' are in the 2- and 7-positions of the 9H-fluorene ring.
- m and n are both zero and R 7 is H.
- R 4 is H and R 8 is phenyl.
- R 4 is H and R 8 is 2-pyridyl.
- R 8 is Re — N R io wherein: R 9 and Rio are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: Rn is selected from the group consisting of H, alkyl, and aryl.
- R 4 and Rg are each H.
- R 4 is ethoxycarbonyl and R 9 is H.
- R-io is H.
- R ⁇ 0 is methyl.
- R ⁇ 0 is isopropyl.
- R ⁇ 0 is methoxyl.
- R ⁇ 0 is iso-butoxyl.
- the fused-ring structure comprises 9/-/-fluoren-9-one.
- a and A' are each independently
- R 4 and R 7 are each independently selected from the group consisting of H alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; and R 8 is selected from the group consisting of aryl and Re — N R M,O wherein: Rg and R ⁇ 0 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: Rn is selected from the group consisting of H, alkyl, and aryl.
- a and A' are in the 2- and 7-positions of the 9H-fluoren- 9-one ring.
- m and n are both zero and R 7 is H.
- R 8 is Re — N R ⁇ n wherein: Rg and R 10 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: Rn is selected from the group consisting of H, alkyl, and aryl.
- Rg and Rio are both H.
- R 4 is H.
- R 4 is ethoxycarbonyl.
- the fused-ring structure comprises 9,10-anthraquinone.
- a and A' are each independently
- R 4 and R 7 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; and R 8 is selected from the group consisting of aryl and
- Rg and R-io are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: Rn is selected from the group consisting of H, alkyl, and aryl. In some embodiments, m and n are both zero and R 7 is H. In some embodiments, R 8 is Re — N ⁇ R 10 wherein: Rg and R 10 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; wherein: Rn is selected from the group consisting of H, alkyl, and aryl. In some embodiments, Rg and R ⁇ 0 are both H. In some embodiments, R 4 is H. In some embodiments of the method of treating a microbial infection by administering to a subject in need of treatment thereof a compound of
- X is N and Y is CH.
- the fused-ring structure comprises acridine.
- a and A' are each independently
- R 4 and R are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; and R 8 is selected from the group consisting of aryl and R 9 — N ⁇ R 10 wherein: R 9 and R ⁇ 0 are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: Rn is selected from the group consisting of H, alkyl, and aryl.
- a and A' are in the 3- and 6-positions of the acridine ring.
- m and n are both zero and R is H.
- R 8 is
- Rg and Rio are each independently selected from the group consisting of H, alkyl, aryl, and -ORn; and wherein: Rn is selected from the group consisting of H, alkyl, and aryl. In some embodiments, Rg and Rio are both H. In some embodiments, R is H.
- the method comprises a compound of Formula I selected from the group consisting of: 2,7-bis-guanidino-9/- -fluorene; 2,7-bis-guanidinofluoren-9- one; 2,7-bis-guanidinoanthraquinone; 3,6-bis-guanidinoacridine; 2,7-bis-( ⁇ /"- ethoxycarbonyl)guanidino-9H-fluorene; 2,7-bis( ⁇ /"- ethoxycarbonyl)guanidinofluoren-9-one; 2,7-bis( ⁇ /"-ethoxycarbonyl- ⁇ /- methyl)guanidino-9H-fluorene; 2,7-bis(/V"-ethoxycarbonyl-/V- isopropyl)guanidino-9H-fluorene; 2,7-bis( ⁇ /"-
- the compound of Formula I is administered in the form of a pharmaceutically acceptable salt.
- the pharmaceutically acceptable salt is a hydrochloride salt.
- the microbial infection is selected from one of a Trypanosoma brucei rhodesiense infection and a Plasmodium falciparum infection.
- the subject treated in the presently disclosed subject matter in its many embodiments is desirably a human subject, although it is to be understood the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term "subject".
- the methods described herein are particularly useful in the treatment and/or prevention of infectious diseases in warm-blooded vertebrates. Thus, the methods can be used as treatment for mammals and birds.
- mammals such as humans, as well as those mammals of importance due to being endangered (such as Siberian tigers), of economical importance (animals raised on farms for consumption by humans) and/or social importance (animals kept as pets or in zoos) to humans, for instance, carnivores other than humans (such as cats and dogs), swine (pigs, hogs, and wild boars), ruminants (such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels), and horses.
- carnivores other than humans such as cats and dogs
- swine pigs, hogs, and wild boars
- ruminants such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels
- kits for treating birds including the treatment of those kinds of birds that are endangered, kept in zoos, as well as fowl, and more particularly domesticated fowl, i.e., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they also are of economical importance to humans.
- embodiments of the methods described herein include the treatment of livestock, including, but not limited to, domesticated swine (pigs and hogs), ruminants, horses, poultry, and the like.
- 2,7-Bis( ⁇ /"-ethoxycarbonylthiourea)-9W-fluorene (6a).
- Two compounds (8a and 5b) show IC-50 values versus Trypanosoma brucei rhodesiense (T.b.r.) at 13 nM or less.
- Two compounds (5a and 8a) show IC-50 values versus Plasmodium falciparum (p.f.) at 10 nM or less.
- Compounds 8a and 8b give 3/4 and 4/4 cures versus the virulent STIP900 strain of T.b.r. in a mouse model. Prodrugs of these compounds hold promise as an oral treatment of both malaria and human African trypanosomiasis.
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Abstract
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EP04811591A EP1689705A4 (en) | 2003-11-24 | 2004-11-18 | Fused ring dicationic anti-protozoan agents and their prodrugs |
JP2006541427A JP2007513888A (en) | 2003-11-24 | 2004-11-18 | Fused ring dicationic antiprotozoal agents and their prodrugs |
CA002547972A CA2547972A1 (en) | 2003-11-24 | 2004-11-18 | Fused ring dicationic anti-protozoan agents and their prodrugs |
AU2004292992A AU2004292992A1 (en) | 2003-11-24 | 2004-11-18 | Fused ring dicationic anti-protozoan agents and their prodrugs |
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EP (1) | EP1689705A4 (en) |
JP (1) | JP2007513888A (en) |
CN (1) | CN1886367A (en) |
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US8158677B2 (en) | 2007-06-01 | 2012-04-17 | The Trustees Of Princeton University | Treatment of viral infections by modulation of host cell metabolic pathways |
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FR2920775B1 (en) * | 2007-09-07 | 2009-11-06 | Pharma Hydro Dev P H D Soc Par | NOVEL DIAMINOPHENOTHIAZINE COMPOUNDS, PROCESS FOR PREPARING THEM AND USES THEREOF. |
US8277026B2 (en) * | 2008-01-16 | 2012-10-02 | Zamtec Limited | Printhead cartridge insertion protocol |
CA2934523A1 (en) | 2013-12-24 | 2015-07-02 | University Of Florida Research Foundation, Inc. | Phenazine derivatives as antimicrobial agents |
WO2017011730A2 (en) * | 2015-07-15 | 2017-01-19 | University Of Florida Research Foundation, Incorporated | Phenazine derivatives as antimicrobial agents |
US11053205B2 (en) | 2017-02-17 | 2021-07-06 | University Of Florida Research Foundation, Incorporated | Phenazine derivatives as antimicrobial agents |
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US1374695A (en) * | 1919-11-21 | 1921-04-12 | Barrett Co | Catalytic oxidation of fluorene |
DE1014518B (en) * | 1956-03-09 | 1957-08-29 | Bayer Ag | Process for coloring and printing polymers and copolymers of acrylonitrile or dicyanaethylene |
US4141992A (en) * | 1975-08-22 | 1979-02-27 | American Cyanamid Company | Cycloalkylcarboxyamidines and halobenzamidines as anti-amebic agents |
US5521190A (en) * | 1993-05-27 | 1996-05-28 | Fmc Corporation | Insecticidal pterdines and 8-deazapteridines |
US5521189A (en) * | 1994-05-06 | 1996-05-28 | The University Of Nc At Ch | Methods of treating pneumocystis carinii pneumonia |
US5677349A (en) * | 1995-04-27 | 1997-10-14 | Gilad; Gad M. | Agmatine for the treatment of neurotrauma and neurodegenerative diseases |
US5668167A (en) * | 1995-06-07 | 1997-09-16 | Duke University | Methods of treating microbial infections |
AU6168296A (en) | 1995-06-07 | 1996-12-30 | The Administrators Of The Tulane Eductional Fund | Chloroquine analogs and methods of preventing and treating p lasmodial disease |
US5628984A (en) * | 1995-07-31 | 1997-05-13 | University Of North Carolina At Chapel Hill | Method of detecting lung disease |
JP2003523927A (en) * | 1998-08-20 | 2003-08-12 | ユニヴァーシティ・オヴ・ノース・キャロライナ・アト・チャペル・ヒル | Dicationic dibenzofuran and dibenzothiophene compounds and their use |
CA2361734A1 (en) * | 1999-01-26 | 2000-10-12 | Andre Rosowsky | Pharmaceutically active compounds and methods of use thereof |
FR2796642B1 (en) * | 1999-07-21 | 2001-10-19 | Centre Nat Rech Scient | QUATERNARY BIS-AMMONIUM SALT PRECURSORS AND THEIR APPLICATIONS AS PRODUCTS HAVING ANTI-PEST CONTROL ACTIVITY |
JP2002097133A (en) * | 2000-07-17 | 2002-04-02 | Shionogi & Co Ltd | Antimalaria agent and nematicidal agent containing triazene compound |
WO2004006842A2 (en) * | 2002-07-11 | 2004-01-22 | Combinatorx, Incorporated | Combinations of drugs for the treatment of neoplasms |
US20050054708A1 (en) * | 2003-07-28 | 2005-03-10 | Nichols Matthew James | Combinations of drugs for the treatment of neoplasms |
ITMI20031754A1 (en) | 2003-09-12 | 2005-03-13 | Fabrizio Marcucci | MICROBICIDE COMPOSITION. |
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Cited By (5)
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US8158677B2 (en) | 2007-06-01 | 2012-04-17 | The Trustees Of Princeton University | Treatment of viral infections by modulation of host cell metabolic pathways |
EP2572712A2 (en) | 2007-06-01 | 2013-03-27 | The Trustees Of Princeton University | Treatment of viral infections by modulation of host cell metabolic pathways |
EP2581081A2 (en) | 2007-06-01 | 2013-04-17 | The Trustees Of Princeton University | Treatment of viral infections by modulation of host cell metabolic pathways |
US9029413B2 (en) | 2007-06-01 | 2015-05-12 | The Trustees Of Princeton University | Treatment of viral infections by modulation of host cell metabolic pathways |
US9757407B2 (en) | 2007-06-01 | 2017-09-12 | The Trustees Of Princeton University | Treatment of viral infections by modulation of host cell metabolic pathways |
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